tert-butyl N-(1,3-dioxoisoindol-2-yl)-N-ethylcarbamate

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Methylhydrazine (1.415 mL, 26.9 mmol) was added to a solution of tert-butyl 1,3-dioxoisoindolin-2-yl(ethyl)carbamate (example 74A, 5.2 g, 17.91 mmol) in THF (40 mL) at 0° C. and the reaction mixture was stirred at room temperature overnight. A white precipitate formed and was filtered off through a pad of Celite, The filtrate was concentrated in vacuo. The residue was dissolved in ethyl acetate (50 ml) and extracted with 1N HCl (3×30 ml), the acid layer was washed with ethyl acetate (50 ml) and basified to pH 10 by addition of 20% NaOH. The basic solution was then extracted with ethyl acetate (3×50 ml) and the combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo to give tert-butyl 1-ethylhydrazinecarboxylate (2.5 g, 87% yield) as colorless oil. A white precipitate formed was filtered off through a pad of Celite The filtrate was concentrated in vacuo The residue was dissolved in ethyl acetate (50 ml) extracted with 1N HCl (3×30 ml) the acid layer was washed with ethyl acetate (50 ml) basified to pH 10 by addition of 20% NaOH The basic solution was then extracted with ethyl acetate (3×50 ml) the combined organic layers were washed with brine dried over magnesium sulfate filtered concentrated in vacuo

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Diisopropyl azodicarboxylate (2.92 mL, 15.00 mmol) was added in one portion to a solution of tert-butyl 1,3-dioxoisoindolin-2-ylcarbamate (2.62 g, 10 mmol, prepared following the procedure described by Nicolas Brosse et al. in Eur. J. Org. Chem. 4757-4764, 2003), triphenylphosphine (3.93 g, 15.00 mmol) and ethanol (0.691 g, 15.00 mmol) in THF (20 mL) at 0° C. and the reaction solution was stirred at room temperature for 1 h (monitored by TLC until completion). Solvent was evaporated and the residue was purified by flash chromatography on silica gel using an automated ISCO system (80 g column, eluting with 5-35% ethyl acetate/hexanes) to provide tert-butyl 1,3-dioxoisoindolin-2-yl(ethyl)carbamate (2.6 g, 90% yield) as a white solid which was used as it in the next step prepared Solvent was evaporated the residue was purified by flash chromatography on silica gel using an automated ISCO system (80 g column, eluting with 5-35% ethyl acetate/hexanes)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Methylhydrazine (1.415 mL, 26.9 mmol) was added to a solution of tert-butyl 1,3-dioxoisoindolin-2-yl(ethyl)carbamate (example 74A, 5.2 g, 17.91 mmol) in THF (40 mL) at 0° C. and the reaction mixture was stirred at room temperature overnight. A white precipitate formed and was filtered off through a pad of Celite, The filtrate was concentrated in vacuo. The residue was dissolved in ethyl acetate (50 ml) and extracted with 1N HCl (3×30 ml), the acid layer was washed with ethyl acetate (50 ml) and basified to pH 10 by addition of 20% NaOH. The basic solution was then extracted with ethyl acetate (3×50 ml) and the combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo to give tert-butyl 1-ethylhydrazinecarboxylate (2.5 g, 87% yield) as colorless oil. A white precipitate formed was filtered off through a pad of Celite The filtrate was concentrated in vacuo The residue was dissolved in ethyl acetate (50 ml) extracted with 1N HCl (3×30 ml) the acid layer was washed with ethyl acetate (50 ml) basified to pH 10 by addition of 20% NaOH The basic solution was then extracted with ethyl acetate (3×50 ml) the combined organic layers were washed with brine dried over magnesium sulfate filtered concentrated in vacuo

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Diisopropyl azodicarboxylate (2.92 mL, 15.00 mmol) was added in one portion to a solution of tert-butyl 1,3-dioxoisoindolin-2-ylcarbamate (2.62 g, 10 mmol, prepared following the procedure described by Nicolas Brosse et al. in Eur. J. Org. Chem. 4757-4764, 2003), triphenylphosphine (3.93 g, 15.00 mmol) and ethanol (0.691 g, 15.00 mmol) in THF (20 mL) at 0° C. and the reaction solution was stirred at room temperature for 1 h (monitored by TLC until completion). Solvent was evaporated and the residue was purified by flash chromatography on silica gel using an automated ISCO system (80 g column, eluting with 5-35% ethyl acetate/hexanes) to provide tert-butyl 1,3-dioxoisoindolin-2-yl(ethyl)carbamate (2.6 g, 90% yield) as a white solid which was used as it in the next step prepared Solvent was evaporated the residue was purified by flash chromatography on silica gel using an automated ISCO system (80 g column, eluting with 5-35% ethyl acetate/hexanes)

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: tert-Butyl 1,3-dioxoisoindolin-2-yl(ethyl)-carbamate (790 mg, 2.7 mmol) in THF (16 mL) was cooled to 0° C. and methylhydrazine (250 μL, 4.8 mmol) was added. The reaction mixture was warmed to room temperature and was stirred until all starting material was consumed. The mixture was filtered through a pad of Celite and the solvent was evaporated. The residue was purified by column chromatography (0-10% methanol in dichloromethane) to afford tert-butyl 1-ethylhydrazinecarboxylate (320 mg, 74%). Retention time: 1.13 minutes (3 min run). was consumed The mixture was filtered through a pad of Celite the solvent was evaporated The residue was purified by column chromatography (0-10% methanol in dichloromethane)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: tert-Butyl 1,3-dioxoisoindolin-2-yl(ethyl)-carbamate (790 mg, 2.7 mmol) in THF (16 mL) was cooled to 0° C. and methylhydrazine (250 μL, 4.8 mmol) was added. The reaction mixture was warmed to room temperature and was stirred until all starting material was consumed. The mixture was filtered through a pad of Celite and the solvent was evaporated. The residue was purified by column chromatography (0-10% methanol in dichloromethane) to afford tert-butyl 1-ethylhydrazinecarboxylate (320 mg, 74%). Retention time: 1.13 minutes (3 min run). was consumed The mixture was filtered through a pad of Celite the solvent was evaporated The residue was purified by column chromatography (0-10% methanol in dichloromethane)

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: tert-Butyl N-(1,3-dioxoisoindolin-2-yl)carbamate (1.0 g, 3.8 mmol), iodoethane (460 μL, 5.7 mmol), potassium carbonate (2.1 g, 15 mmol), and benzyl-triethyl-ammonium bromide (210 mg, 0.80 mmol) were combined in acetonitrile (15 mL) and heated at 50° C. for 48 h. The reaction mixture was diluted with water (30 mL) and was extracted with ether (3×15 mL). The combined organics were washed with brine, dried over sodium sulfate and evaporated to dryness. The crude material was purified by column chromatography (0-20% ethyl acetate in hexanes) to afford tert-butyl 1,3-dioxoisoindolin-2-yl(ethyl)-carbamate (0.79 g, 71%). ESI-MS m/z calc. 290.1, found 291.3 (M+1)+; Retention time: 1.64 minutes (3 min run). 1H NMR (400 MHz, CDCl3) δ 7.98-7.85 (m, 2H), 7.84-7.69 (m, 2H), 3.86-3.57 (m, 2H), 1.52 (s, 3H), 1.32 (s, 6H), 1.27-1.04 (m, 3H). was extracted with ether (3×15 mL) The combined organics were washed with brine dried over sodium sulfate evaporated to dryness The crude material was purified by column chromatography (0-20% ethyl acetate in hexanes)

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: tert-Butyl N-(1,3-dioxoisoindolin-2-yl)carbamate (1.0 g, 3.8 mmol), iodoethane (460 μL, 5.7 mmol), potassium carbonate (2.1 g, 15 mmol), and benzyl-triethyl-ammonium bromide (210 mg, 0.80 mmol) were combined in acetonitrile (15 mL) and heated at 50° C. for 48 h. The reaction mixture was diluted with water (30 mL) and was extracted with ether (3×15 mL). The combined organics were washed with brine, dried over sodium sulfate and evaporated to dryness. The crude material was purified by column chromatography (0-20% ethyl acetate in hexanes) to afford tert-butyl 1,3-dioxoisoindolin-2-yl(ethyl)-carbamate (0.79 g, 71%). ESI-MS m/z calc. 290.1, found 291.3 (M+1)+; Retention time: 1.64 minutes (3 min run). 1H NMR (400 MHz, CDCl3) δ 7.98-7.85 (m, 2H), 7.84-7.69 (m, 2H), 3.86-3.57 (m, 2H), 1.52 (s, 3H), 1.32 (s, 6H), 1.27-1.04 (m, 3H). was extracted with ether (3×15 mL) The combined organics were washed with brine dried over sodium sulfate evaporated to dryness The crude material was purified by column chromatography (0-20% ethyl acetate in hexanes)